At a Glance

Maple Syrup Urine Disease (MSUD) is an inherited disorder of metabolism of the essential amino acids leucine, isoleucine, and valine due to a defect in branched-chain alpha-keto acid dehydrogenase complex. These three branched-chain amino acids (BCAA) are present in all protein containing foods, and individuals with MSUD will have elevated levels of all three.

MSUD is inherited in an autosomal recessive manner. Autosomal recessive inheritance means the individual has inherited two abnormal copies of the gene (each gene containing a mutation), causing MSUD. MSUD may be caused by one of three different genes: BCKDHA, BCKDHB, and DBT. Both parents of an individual with MSUD are carriers and do not manifest any symptoms of disease.

MSUD may present with four different forms. Classic MSUD often presents in the newborn period, typically during the first week of life—even as early as 2 days of life; intermediate MSUD may present at any age; intermittent MSUD may only manifest with episodes of ataxia and ketoacidosis associated with triggering illnesses; and the fourth form of MSUD is thought to be responsive to thiamine supplementation. Untreated patients typically exhibit a specific maple syrup (sweet or caramel-like has been described) smell in their urine or cerumen due to elevations in 4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone). Affected infants exhibit encephalopathy with ketoacidosis.

There may be no readily apparent trigger in this newborn time, but the worsening of symptoms is relentless. Infants have decreased responsiveness, irritability, and poor feeding and will progress to coma. Respiratory distress, bradycardia, hiccups, and hypothermia appear as cerebral edema increases (often called “leucinosis”). Movements described as “fencing” or “bicycling” may occur with apnea and opisthotonus. The edema is thought to be due to electrolyte imbalances resulting from accumulations of branched-chain ketoacids (BCKA) and amino acids. Specifically, leucine and 2-ketoisocaproic acid (2 of the BCKAs) are thought to contribute to cerebral edema and toxicity. Valine and isoleucine and their respective keto-acid metabolites are not thought to contribute significantly to toxicity.

Other disorders that may cause acute encephalopathy, such as viral and bacterial meningitis, drug toxicity, and overdose, as well as inherited disorders causing severe metabolic acidosis, lactic acidosis, and/or hyperammonemia must be considered.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

MSUD is diagnosed through detection of elevated BCAAs: leucine, isoleucine, and valine. Alloisoleucine is also found in all affected patients with severe and milder forms when they are not restricting dietary protein. Elevations are detected on standard quantitative plasma amino acid analysis. Alloisoleucine may also coelute with other amino acids, most commonly isoleucine or cystathionine, making detection and quantification difficult. If clinical suspicion is high, the Biochemical Genetics Laboratory Director should be contacted for specific discussion and review of the chromatogram.

Additional laboratory testing includes urine organic aids, which will demonstrate elevation of derivative 2-keto- and 2-hydroxy-BCKAs. Bedside urine ketone measurement may be helpful for immediate detection of elevated ketoacids, either at home or in the clinic or hospital, thereby expediting rapid treatment in known patients. Dinitrophenylhydrazine (DNPH) may be added to urine and will produce a yellow-white precipitate if these BCKAs are present.

Serum electrolytes, lactate, plasma ammonia, acylcarnitines, renal function, complete blood count (CBC), liver function, and coagulation parameters should be checked to assess for underlying illness and in case of the need for dialysis.

Newborn screening panels have now been expanded in all states in the United States and in most developed nations to include measurement of BCAAs. Detection and quantitation of alloisoleucine is difficult and is only possible in certain centers. An infant with an elevation of leucine/isoleucine and valine on newborn screening should have immediate clinical evaluation and plasma amino acid analysis.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Individuals who have equivocal results should have testing repeated, following protein intake if fasting or within the first day of life. Levels of alloisoleucine less than 5 µM should be repeated and clinically correlated with the referring physician. If possible, samples should be collected during acute symptoms when results are unclear or the clinical description is inconsistent.

Elevations of BCAA without alloisoleucine may also be seen in individuals with severe metabolic ketoacidosis or prolonged fasting. Those with suspected milder forms should still have detectable alloisoleucine greater than 5 µM.

If the newborn screening sample or plasma amino acids are collected before sufficient feeding with protein, the levels of BCAAs may not be elevated.

What Lab Results Are Absolutely Confirmatory?

Plasma amino acids with detection of elevated BCAA and alloisoleucine is sufficient for diagnosis. Further confirmation through DNA sequencing is also available.

Although MSUD is typically rare, with an incidence of about 1 in 180,000 live births, founder mutations are common in Mennonite populations of Pennsylvania, Ohio, Indiana, Michigan, Kentucky, Wisconsin, and New York with an incidence of about 1 in 380 live births. Most mutations are unique, and compound heterozygotes with mutations in different genes have been reported.

Enzyme analysis can be done in liver tissue, white blood cells, or skin fibroblasts but is not typically necessary.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Rapid initiation of treatment at diagnosis, as well as during any acute event, is critical. Elevations of leucine and 2-ketoisocaproic acid are specifically neurotoxic, and brain injury is progressive. Affected individuals are placed on low-protein BCAA-free diets with strict control of leucine intake. Monitoring with regular measurement of plasma amino acids, electrolytes, minerals, micronutrients, prealbumin, albumin, iron, hemoglobin, and essential fatty acids are critical to ensure proper clinical growth and development. Deficiencies should be promptly treated. Ongoing clinical management with close monitoring of dietary protein is important to ensure adequate growth and development.

Treatment during acute events includes removal of protein intake and possibly hemodialysis to reduced accumulated leucine and ketoacids. Precautions to monitor intracranial pressure with frequent neurological exams and monitoring for cerebral edema is mandatory. Adequate rehydration with normal saline bolus fluids should be followed by infusion of nonprotein calories, such as 10% dextrose intravenous solutions, intravenous intralipids, and nasogastric feeding with BCAA-free formula. Intravenous insulin drip may also be used to promote an anabolic metabolic state. Supplementation with solutions of isoleucine and valine may also help promote protein synthesis and decrease levels of leucine.

Long-term morbidity can include osteoporosis, and recurrent Candida infections may occur from inadequate nutrition. Other reports have shown an increase in acute pancreatitis that may be difficult to detect in an acutely ill and vomiting individual.

In addition to the classic severe form, there are other forms due to residual enzyme activity. Intermediate MSUD may present later in life with developmental delay, poor feeding, and weight gain. These individuals are still at risk for severe neurological sequelae due to cerebral edema when they are significantly stressed and catabolic. Management and monitoring of these individuals is the same as the classic form.

A milder intermittent MSUD may also face severe acute leucinosis but will have a history of normal development and growth. They may only have mild elevations of BCAAs when healthy but will manifest more classic symptoms and laboratory abnormalities during catabolic stress.

A thiamine-responsive form of MSUD has been described. Thiamine is a cofactor for the enzyme complex and is thought to be beneficial in individuals with higher residual enzyme levels. However, studies have not shown any specific benefit of thiamine as individuals were also treated with a BCAA-restricted diet. Although a trial of thiamine supplementation seems reasonable, no clinical efficacy has been seen.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Urine amino acids may not adequately quantitate elevated BCAA levels.

The odor of sotolone may also be detected in individuals who have ingested fenugreek and lovage. Other odors, such as scented diapers or cleaning agents, may also produce a “maple syrup” odor and are frequently reported by parents.